1. Field of the Invention
The present invention is directed to prodrugs of proton pump inhibitors which are usefull as anti-ulcer agents. More particularly, the present invention is directed to prodrugs that slowly hydrolyze to provide benzimidazole-type proton pump inhibitors which inhibit exogenously or endogenously gastric acid secretion and thus can be used in the prevention and treatment of gastrointestinal inflammatory diseases in mammals, including humans.
2. Brief Description of the Prior Art
Benzimidazole derivatives intended for inhibiting gastric acid secretion are disclosed in the U.S. Pat. Nos. 4,045,563; 4,255,431; 4,628,098; 4,686,230; 4,758,579; 4,965,269; 5,021,433; 5,430,042 and 5,708,017. Generally speaking, the benzimidazole-type inhibitors of gastric acid secretion work by undergoing a rearrangement to form a thiophilic species which then covalently binds to gastric H,K-ATPase, the enzyme involved in the final step of proton production in the parietal cells, and thereby inhibits the enzyme. Compounds which inhibit the gastric H,K-ATPase enzyme are generally known in the field as "proton pump inhibitors" (PPI).
Some of the benzimidazole compounds capable of inhibiting the gastric H,K-ATPase enzyme have found substantial use as drugs in human medicine and are known under such names as
LANSOPRAZOLE (U.S. Pat. No. 4,628,098), PA1 OMEPRAZOLE (U.S. Pat. Nos. 4,255,431 and 5,693,818), PA1 PANTOPRAZOLE (U.S. Pat. No. 4,758,579), and PA1 RABEPRAZOLE (U.S. Pat. No. 5,045,552). PA1 R.sub.1, R.sub.2 and R.sub.3 are independently selected from hydrogen, alkyl of 1 to 10 carbons, fluoro substituted alkyl of 1 to 10 carbons, alkoxy of 1 to 10 carbons, fluoro substituted alkoxy of 1 to 10 carbons, alkylthio of 1 to 10 carbons, fluoro substituted alkylthio of 1 to 10 carbons, alkoxyalkoxy of 2 to 10 carbons, amino, alkylamino and dialkylamino each of the alkyl groups in said alkylamino and dialkyl amino groups having 1 to 10 carbons, halogen, phenyl, alkyl substituted phenyl, alkoxy substituted phenyl, phenylalkoxy, each of the alkyl groups in said alkyl substituted phenyl, alkoxy substituted phenyl and phenylalkoxy having 1 to 10 carbons, piperidino, morpholino or two of the R.sub.1, R.sub.2 and R.sub.3 groups jointly forming a 5 or 6 membered ring having 0 or 1 heteroatom selected from N, S and O; PA1 R.sub.4 and R.sub.5 are independently selected from hydrogen, alkyl of 1 to 10 carbons, fluoro substituted alkyl of 1 to 10 carbons, phenylalkyl, naphthylalkyl and heteroarylalkyl, alkyl in said phenylalkyl, naphthylalkyl and heteroarylalkyl groups having 1 to 10 carbons; PA1 R.sub.6, is hydrogen, halogen, alkyl of 1 to 10 carbons, fluoro substituted alkyl of 1 to 10 carbons, alkoxy having 1 to 10 carbons or fluoro substituted alkoxy having 1 to 10 carbons; PA1 R.sub.6 through R.sub.9 are independently selected from hydrogen, alkyl of 1 to 10 carbons, halogen substituted alkyl of 1 to 10 carbons, alkoxy of 1 to 10 carbons, halogen substituted alkoxy of 1 to 10 carbons, alkylcarbonyl, alkoxycarbonyl the alkyl group in said alkylcarbonyl and alkoxycarbonyl having 1 to 10 carbons, oxazolyl, imidazolyl, thiazolyl, pyrazolyl, or any two adjacent ones of the R.sub.6 through R.sub.9 groups may form a ring that may optionally include a heteroatom selected from N, O and S and said ring may be further substituted; PA1 R.sub.10 is hydrogen, alkyl of 1 to 10 carbons, or R.sub.10 may form an alkylene chain together with R.sub.3, PA1 R.sub.11 and R.sub.12 are independently selected from hydrogen, halogen, alkyl of 1 to 10 carbons and halogen substituted alkyl of 1 to 10 carbons; ##STR2## where R.sub.16 is alkyl of 1 to 10 carbons, morpholino, piperidino, phenyl, naphthyl or heteroaryl having 1 to 3 heteroatoms selected from N, O or S, said morpholino, piperidino phenyl, naphthyl or heteroaryl groups being unsubstituted, or substituted with 1 to 5 R.sub.17 groups; PA1 R.sub.17 is alkyl of 1 to 10 carbons, halogen substituted alkyl of 1 to 10 carbons, alkoxy having 1 to 10 carbons, halogen substituted alkoxy of 1 to 10 carbons, alkylthio having 1 to 10 carbons, halogen substituted alkylthio of 1 to 10 carbons, alkoxy carbonyl having 1 to 10 carbons, halogen substituted alkoxy carbonyl having 1 to 10 carbons, F, Cl, Br, I, NO.sub.2, CN, OCOalkyl, NH.sub.2, alkylamino and dialkylamino where in said OCOalkyl,, alkylamino and dialkylamino groups each of said alkyl group has 1 to 10 carbons; PA1 R.sub.18 is independently selected from H, alkyl of 1 to 10 carbons and phenyl; PA1 R.sub.19 and R.sub.20 are independently selected from H, alkyl of 1 to 10 carbons, halogen substituted alkyl of 1 to 10 carbons, or R.sub.19 and R.sub.20 together with the N atom may form a 4 to 10 membered ring that may include one more heteroatom selected from N, O or S, said N heteroatom being unsubstituted or substituted with an alkyl group of 1 to 10 carbons, or with an aryl or heteroaryl group, and PA1 R.sub.21 is phenyl, naphthyl or heteroaryl having 1 to 3 heteroatoms independently selected from N, O and S, said phenyl, naphthyl or heteroaryl groups being unsubstituted or substituted with 1 to 5 R.sub.17 groups, PA1 Y is O or .dbd.NR.sub.16, PA1 or to a pharmaceutically acceptable salt of said compounds. PA1 1-benzenesulfonyl-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulf inyl]-1H-benzimidazole, PA1 1-benzenesulfonyl-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulf inyl]-1H-benzimidazole, PA1 1-benzenesulfonyl-5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfi nyl]-1H-benzimidazole, PA1 1-benzenesulfonyl-6-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfi nyl]-1H-benzimidazole, PA1 1-benzenesulfonyl-2-[(3-methyl-4-(2',2',2'-trifluoroethoxy)-2-pyridyl)methy lsulfinyl]-1H-benzimidazole, PA1 1-(p-chlorobenzenesulfonyl)-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl]-1H-benzimidazole, PA1 1-(p-chlorobenzenesulfonyl)-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl]-1H-benzimidazole, PA1 1-(p-chlorobenzenesulfonyl)-5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)m ethylsulfinyl]-1H-benzimidazole, PA1 1-(p-chlorobenzenesulfonyl)-6-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)m ethylsulfinyl]-1H-benzimidazole, PA1 1-(p-chlorobenzenesulfonyl)-2-[(3-methyl-4-(2',2',2'-trifluoroethoxy)-2-pyr idyl)methylsulfinyl]-1H-benzimidazole, PA1 1-(p-bromobenzenesulfonyl)-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)m ethylsulfinyl]-1H-benzimidazole, PA1 1-(p-bromobenzenesulfonyl)-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)m ethylsulfinyl]-1H-benzimidazole, PA1 1-(p-bromobenzenesulfonyl)-5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)me thylsulfinyl]-1H-benzimidazole, PA1 1-(p-bromobenzenesulfonyl)-6-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)me thylsulfinyl]-1H-benzimidazole, PA1 1-(p-bromobenzenesulfonyl)-2-[(3-methyl-4-(2',2',2'-trifluoroethoxy)-2-pyri dyl)methylsulfinyl]-1H-benzimidazole, PA1 1-(p-fluorobenzenesulfonyl)-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl]-1H-benzimidazole, PA1 1-(p-fluorobenzenesulfonyl)-6-methoxy-2-[(3,5dimethyl-4-methoxy-2-pyridyl)m ethylsulfinyl]-1H-benzimidazole, PA1 1-(p-fluorobenzenesulfonyl)-5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)m ethylsulfinyl]-1H-benzimidazole, PA1 1-(p-fluorobenzenesulfonyl)-6-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)m ethylsulfinyl]-1H-benzimidazole, PA1 1-(p-fluorobenzenesulfonyl)-2-[(3-methyl-4-(2',2',2'-trifluoroethoxy)-2-pyr idyl)methylsulfinyl]-1H-benzimidazole, PA1 1-(p-methylbenzenesulfonyl)-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl]-1H-benzimidazole, PA1 1-(p-methylbenzenesulfonyl)-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl]-1H-benzimidazole, PA1 1-(p-methylbenzenesulfonyl)-5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)m ethylsulfinyl]-1H-benzimidazole, PA1 1-(p-methylbenzenesulfonyl)-6-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)m ethylsulfinyl]-1H-benzimidazole, PA1 1-(p-methylbenzenesulfonyl)-2-[(3-methyl-4-(2',2',2-trifluoroethoxy)-2-pyri dyl)methylsulfinyl]-1H-benzimidazole, PA1 1-(p-methoxybenzenesulfonyl)-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl )methylsulfinyl]-1H-benzimidazole, PA1 1-(p-methoxybenzenesulfonyl)-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl )methylsulfinyl]-1H-benzimidazole, PA1 1-(p-methoxybenzenesulfonyl)-5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl) methylsulfinyl]-1H-benzimidazole, PA1 1-(p-methoxybenzenesulfonyl)-6-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl) methylsulfinyl]-1H-benzimidazole, PA1 1-(p-methoxybenzenesulfonyl)-2-[(3-methyl-4-(2',2'-trifluoroethoxy)-2-pyrid yl)methylsulfinyl]-1H-benzimidazole, PA1 1-(3-trifluoromethylbenzenesulfonyl)-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2 -pyridyl)methylsulfinyl]-1H-benzimidazole, PA1 1-(3-trifluoromethylbenzenesulfonyl)-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2 -pyridyl)methylsulfinyl]-1H-benzimidazole, PA1 1-(3-trifluoromethylbenzenesulfonyl)-5-difluoromethoxy-2-[(3,4-dimethoxy-2- pyridyl)methylsulfinyl]-1H-benzimidazole, PA1 1-(3-trifluoromethylbenzenesulfonyl)-6-difluoromethoxy-2-[(3,4-dimethoxy-2- pyridyl)methylsulfinyl]-1H-benzimidazole, PA1 1-(3-trifluoromethylbenzenesulfonyl)-2-[(3-methyl-4-(2',2',2'-trifluoroetho xy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole, PA1 1-(p-trifluoromethoxybenzenesulfonyl)-5-methoxy-2-[(3,5-dimethyl-4-methoxy- 2-pyridyl)methylsulfinyl]-1H-benzimidazole, PA1 1-(p-trifluoromethoxybenzenesulfonyl)-6-methoxy-2-[(3,5-dimethyl-4-methoxy- 2-pyridyl)methylsulfinyl]-1H-benzimidazole, PA1 1-(p-trifluoromethoxybenzenesulfonyl)-5-difluoromethoxy-2-[(3,4-dimethoxy-2 -pyridyl)methylsulfinyl]-1H-benzimidazole, PA1 1-(p-trifluoromethoxybenzenesulfonyl)-6-difluoromethoxy-2-[(3,4-dimethoxy-2 -pyridyl)methylsulfinyl]-1H-benzimidazole, PA1 1-(p-trifluoromethoxybenzenesulfonyl)-2-[(3-methyl-4-(2',2',2'-trifluoroeth oxy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole, PA1 1-(p-dimethylaminobenzenesulfonyl)-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-p yridyl)methylsulfinyl]-1H-benzimidazole, PA1 1-(p-dimethylaminobenzenesulfonyl)-5-difluoromethoxy-2-[(3,4-dimethoxy-2-py ridyl)methylsulfinyl]-1H-benzimidazole, PA1 1-(p-dimethylaminobenzenesulfonyl)-2-[(3-methyl-4-(2',2',2'-trifluoroethoxy )-2-pyridyl)methylsulfinyl]-1H-benzimidazole, PA1 1-(p-ethoxycarbonylbenzenesulfonyl)-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2- pyridyl)methylsulfinyl]-1H-benzimidazole, PA1 1-(p-ethoxycarbonylbenzenesulfonyl)-2-[(3-methyl-4-(2',2',2'-trifluoroethox y)-2-pyridyl)methylsulfinyl]-1H-benzimidazole.
The diseases treated by proton pump inhibitors and specifically by the four above-mentioned drugs include peptic ulcer, heart burn, reflux esophagitis errosive esophagitis, non-ulcer dispepsia, infection by Helicobacter pylori, alrynitis and asthma among others.
Whereas the proton pump inhibitor type drugs represent substantial advance in the field of human and veterinary medicine, they are not totally without shortcomings or disadvantages. The shortcomings of the presently used proton pump inhibitor (PPI) type drugs can be best explained by a more detailed description of the mode of their action, the diseases or condition against which they are employed and the circumstances of their application. Thus, acid related diseases include but are not limited to errosive esophagitis, esophageal reflux, gastric and duodenal ulcer, non-ulcer dyspepsia and infection by Helicobacter pylori. Current therapy of all but the infection by H. pylori bacteria involves treatment with drugs designed to suppress acid secretion, one type of which are the above-mentioned proton pump inhibitors.
The presently used proton pump inhibitors are pyridyl methyl sulfinyl benzimidazoles (or compounds of closely related structure) with a pK.sub.a of 4.0 to 5.0. Their mechanism of action requires accumulation in the acidic space of the parietal cell (secretory canaliculus, pH ca. 1.0) and subsequently hydrogen ion catalyzed conversion to the reactive thiophilic species that is capable of inhibiting the gastric ATPase, enzyme resulting in effective inhibition of gastric secretion. Because of this mechanism the presently used PPI type drugs require specialized gastro protection to remain active for duodenal absorption. For this reason, and due to sensitivity to degradation in the acid milieu of the stomach, oral formulations of the PPI drugs are usually enteric coated. The need for enteric coating is a shortcoming because enteric coating is expensive and moisture sensitive.
Because of the requirement for accumulation in the acid space of the parietal cell, acid secretion is necessary for the efficacy of the PPI type drugs. It was found that the plasma half life of these drugs is between 60 to 90 minutes. All acid pumps are not active at any one time, rather only about 75% are active on the average during the time the drug is present in the blood following oral administration. It was also found in medical experience that on a currently used once-a-day oral administration therapy the maximal inhibition of stimulated acid output is approximately 66%. This is due to a combination of the short plasma half life of the drug, to the limited number of acid pumps active during presentation of the drug and to the turn-over of acid pumps. In present practice it is not possible to control night time acid secretion by evening therapy of oral administration because the drug is dissipated from the plasma by the time acid secretion is established after midnight.
The ideal target for healing in acid related diseases and for treatment of H. pylori infection (in conjunction with antibiotics), as well as for relief of symptoms of non-ulcer dyspepsia would be full inhibition of acid secretion. With the currently used PPI type drugs this is achieved only by intravenous infusion; in case of the drug OMEPRAZOLE this requires intravenous infusion of 8 mg per hour. Clearly, there is a need in the art for a drug or drugs acting through the mechanism of PPI-type drugs which can attain or approach full inhibition of acid secretion through oral therapy.
Because of the less than full inhibition of acid secretion and less than 24 hour inhibition through oral administration that is attained by the current dosage forms of currently used PPI-type drugs, therapy for healing of gastric and duodenal ulcerations is 4 to 8 weeks. This is in spite of the fact that the generation time of surface cells of the esophagus, stomach and duodenum is approximately 72 hours. Undoubtedly the presently observed prolonged healing times with these drugs is due to inadequate acid suppression and acid related damage. The foregoing underscores the need in the art for a drug or drugs acting through the mechanism of PPI-type drugs which can attain or approach full inhibition of acid secretion through oral therapy.
As further pertinent background to the present invention, applicants note the concept of prodrugs which is well known in the art. Generally speaking, prodrugs are derivatives of per se drugs, which after administration undergo conversion to the physiologically active species. The conversion may be spontaneous, such as hydrolysis in the physiological environment, or may be enzyme catalyzed. From among the voluminous scientific literature devoted to prodrugs in general, the foregoing examples are cited: Design of Prodrugs (Bundgaard H. ed.) 1985 Elsevier Science Publishers B. V. (Biomedical Division), Chapter 1; Design of Prodrugs: Bioreversible derivatives for various functional groups and chemical entities (Hans Bundgaard); Bundgaard et al. Int. J. of Pharmaceutics 22 (1984) 45-56 (Elsevier); Bundgaard et al. Int. J. of Pharmaceutics 29 (1986) 19-28 (Elsevier); Bundgaard et al. J. Med. Chem. 32 (1989) 2503-2507 Chem. Abstracts 93, 137935y (Bundgaard et al.); Chem. Abstracts 95, 138493f (Bundgaard et al.); Chem. Abstracts 95, 138592n (Bundgaard et al.); Chem. Abstracts 110, 57664p (Alminger et al.); Chem. Abstracts 115, 64029s (Buur et al.); Chem. Abstracts 115, 189582y (Hansen et al.); Chem. Abstracts 117, 14347q (Bundgaard et al.); Chem. Abstracts 117, 55790x (Jensen et al.); and Chem. Abstracts 123, 17593b (Thomsen et al.).
As far as the present inventors are aware, there are no prodrugs of the proton pump inhibitors presently in use. However, several United States patents describe compounds which can act as prodrugs of certain proton pump inhibitors. Specifically, U.S. Pat. No. 4,686,230 (Rainer et al.) describes derivatives of pyridyl methyl sulfinyl benzimidazoles which include a group designated "R.sub.5 " on one of the benzimidazole nitrogens. The "R.sub.5 " group is expected to cleave under physiological condition, or under the influence of an enzyme to provide the corresponding compound with a free N-H bond (see column 3 of U.S. Pat. No. 4,686,230). U.S. Pat. Nos. 5,021,433 (Alminger et al.), 4,045,563 (Bemtsson et al.), 4,965,269 and (Brandstrom et al.) also describe pyridyl methyl sulfinyl benzimidazoles where one of the nitrogens of the benzimidazole moiety bears a substituent that cleaves under physiological or enzymatic conditions.
The present invention represents further advance in the art in that it provides prodrugs of improved structure of the proton pump inhibitor type drugs and provides proof of the suitability of the prodrugs of the invention for use as prodrug of proton pump inhibitors, with improved efficacy in therapy of acid related diseases due to prolongation of the presence of the proton pump inhibitors in the body.